Pooling-based genome-wide association study implicates gamma-glutamyltransferase 1 (GGT1) gene in pancreatic carcinogenesis

Abstract

Background/aims: Knowledge regarding genetic factors that influence pancreatic cancer risk is currently limited. To identify novel pancreatic cancer susceptibility loci, we conducted a two-stage genome-wide association study.

Methods: The Affymetrix Genome-Wide Human SNP Array 6.0 and DNA pooling were used in the screening stage. Twenty-six single-nucleotide polymorphisms (SNPs) were selected for follow-up. These 26 lead SNPs and additionally selected tagSNPs for the regions around the lead SNPs were evaluated by individual genotyping of the pooling population and an independent validation population.

Results: Of the lead SNPs, the strongest association was found with rs4820599 located in the gamma-glutamyltransferase 1 (GGT1) gene. This SNP was significantly associated with pancreatic cancer risk in the validation population and the combined dataset (p(allele-based) = 0.019 and p(allele-based) = 0.003, respectively). Statistically significant associations were also observed with two GGT1 tagSNPs: rs2017869 and rs8135987. Lead SNP rs4820599 is in high linkage disequilibrium (LD; pairwise r(2): 0.69) and tagSNP rs2017869 is in strong LD (pairwise r(2): 0.96) with SNP rs5751901, which has been reported to be associated with increased GGT1 serum levels. GGT is expressed in the pancreas and plays a key role in glutathione metabolism.

Conclusion: Our results suggest that common variation in the GGT1 gene may affect the risk of pancreatic cancer. .

Fig. 1

Pooling-based GWA results. Each chromosome (Chr) is depicted as a different color. The p values shown are for ranking purposes only; they are based on a t test analysis (comparing allele frequency estimates in case and control pools) that overstates the statistical significance. The upper horizontal line (red in the online version) indicates the p value threshold (1 × 10⁻⁵) used for selecting SNPs for follow-up.